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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The question of possible earlier and more aggressive recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation (LDLT) compared to deceased donor liver transplantation (DDLT) remains unanswered. To address this issue we retrospectively reviewed virological, histological, and clinical data in 67 patients (52 DDLT and 15 LDLT) who underwent liver transplant for their HCV-related cirrhosis since April 2001. Our data indicate that there is no statistical difference between LDLT and DDLT groups in mean age, Child-Turcotte-Pugh score, model for end-stage liver disease score, and gender distribution. The mean follow-up was 749 ± 371 days in LDLT and 692 ± 347 days in DDLT. The predominant genotype in the LDLT and DDLT are genotype 1 (LDLT, 91%; DDLT, 70%). All patients with histologically confirmed recurrent HCV had detectable HCV-RNA in serum. The histological recurrence rate of hepatitis C was 58% at 4 months, 90% at 1 year, and 100% at 2 years in LDLT patients vs. 71% at 4 months, 94% at 1 year, and 95% at 2 years in DDLT patients (not significant) Comparison of the activity of inflammation and fibrosis score at all time points failed to show a statistical difference. Kaplan-Meier survival analysis showed similar patient and graft survival rates between the 2 groups. Our data indicate that histological recurrence of HCV is an early event and virtually universal 2 years' posttransplantation, regardless of modality of donor procurement. Liver Transpl 12:560–565, 2006. © 2006 AASLD.

Hepatitis C virus (HCV) infection-related end-stage liver disease is the leading indication for liver transplantation (LT) in the United States and is expected to increase significantly by the year 2008.1–3 Growth in organ demand will worsen the already critically limited supply of grafts for those in need of a liver transplant. Over the last decade, living donor liver transplantation (LDLT) has been embraced as an alternative option to increase the availability of organs and address the needs of patients who cannot await a deceased donor liver transplantation (DDLT). This relatively new approach presents similar short-term patient and graft outcomes to DDLT.4

As with all patients infected with HCV, the critical issue is how to address the inexorable progression of HCV disease after surgery. In the DDLT recipient, it is an almost universal phenomenon with histological recurrence rate of more than 30% in patients 1 year post-LT.5 The natural history of post-LT HCV in conventional recipients has been demonstrated to involve rapid progression to cirrhosis in 6 to 23% of patients with a median of 3 to 4 years post-LT.6–11 The cumulative probability of developing graft cirrhosis is estimated to reach 30% at 5 years.7 The 1- and 5-year actuarial risk of decompensation is estimated at 42 and 62%, respectively.12 As many as 10 to 25% of patients will meet criteria for retransplantation within 5 years of LT.

Early reports have indicated that recurrence of HCV infection in LDLT recipients has an earlier and more aggressive clinical course compared to recurrence in the DDLT recipient.13, 14 This phenomenon has been attributed to rapid graft regeneration and inflammation accompanied by poor graft function in the early postoperative period.13, 14 The clinical practice in many programs has been significantly modified by their initial experience. However, significant conflicting evidence has also surfaced.15–19 The reasons for these discrepant reports remains unclear at this time.

In the present report, we compared the recurrence rate of hepatitis C, disease severity and progression, clinical outcomes and survival between LDLT and DDLT recipients at 4 months, 1 year, and 2 years using all available clinical information. Our center performs protocol liver biopsies, and we believe that the use of histological data will prove pivotal to delineating the course of HCV recurrence in this subset of patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

An adult LDLT program was instituted in our center in April 2001. Since that time and until November 2004, 83 patients underwent LT for HCV-related end-stage liver disease. With Mayo Clinic Foundation Institutional Review Board approval, a retrospective review of the clinical course in these patients was conducted. We selected our study population by using the following criteria. All study patients had (1) greater than 6 months' follow-up with available protocol liver biopsy or biopsies, (2.) absence of human immunodeficiency virus/hepatitis B virus infection before and after liver transplantation, (3.) no ongoing acute or chronic rejection, and (4.) no active cytomegalovirus infection or primary graft nonfunction. Fifty-two patients received deceased donor grafts and 15 patients received living donor grafts. A total of 16 patients were not considered for analysis.

Recurrent HCV infection was diagnosed by evidence of viral replication, biochemical injury markers, and confirmatory histology.

Immunosuppression

Most patients were on our standard immunosuppression protocol, which consists of tacrolimus (target level range at >3 months, 8-12 ng/mL) along with oral steroids (prednisone) during the first 4 months post-LT. Patients with renal insufficiency received mycophenolate mofetil (0.5-1 g BID) along with reduced tacrolimus levels (range, 5-8 ng/mL). Rejection episodes were treated with high-dose intravenous methylprednisolone (1,000 mg) every other day for a total of 3 doses. No steroid-resistant rejection occurred during the study period. Because of an ongoing clinical trial, 10 patients received daclizumab (Zenapax) induction therapy at time of transplantation. Of those, 3/15 (20%) were in the LDLT group and 7/52 (13.5%) were in the DDLT group. The patients were assigned randomly to a daclizumab-containing regimen, and the difference in distribution was not statistically significant (P = 0.6) for the purposes of our study.

Data Collection

Variables collected included patient and donor demographics, secondary diagnoses before and after LT, viral load (measured by COBAS Amplicor [Roche Diagnostics, Alameda, CA, USA] HCV polymerase chain reaction RNA), genotype (determined by using the INNO-LiPA [Innogenetics, Ghent, Belgium]), hepatic injury markers and synthetic tests before and after LT, histological data, immunosuppressant information, and posttransplantation complications.

Histological Evaluation

Liver biopsies were performed per institutional protocol at postreperfusion, day 7, 4 months, and yearly thereafter. Additional biopsies were performed when clinically indicated. Our histological definition of viral recurrence consists of the presence of lobular activity (eosinophilic bodies, lymphocytic infiltrate in the lobule, and hepatocellular damage) and portal inflammation lacking diagnostic features of rejection. All biopsies were interpreted by a single pathologist who was unaware of the biochemical and virological status of the patients. Recurrence of HCV is defined as the presence of lobular activity and portal inflammation with no diagnostic feature of rejection. Hepatitis disease severity was scored using the Batts-Ludwig schema.20

Statistical Analysis

All statistical analysis was performed using SPSS Statistical Software for Windows, version 11.0 (SPSS Inc., Chicago, IL). The Kaplan-Meier test was used for analysis of patient and graft survival during the follow-up period of time. Student's t test was used when indicated. Results were considered statistically significant at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographic Data of LDLT and CDLT Recipients (Table 1)

From a total of 83 transplanted patients, 67 were evaluated for this study. The median follow-up was 692 ± 347 days and 749 ± 371 days for DDLT and LDLT, respectively. Fifty-two patients received DDLT and 15 patients received LDLT, with similar age and gender distributions. The mean ages for the DDLT and LDLT groups were 51.0 ± 5.4 (36-64) and 51.4 ± 8.2 (28-65) years at time of transplant, respectively. The mean Child-Turcotte-Pugh and model for end-stage liver disease scores were slightly higher in the DDLT group than in the LDLT group (not significant). Additionally, 26.7% of LDLT recipients and 36.5% of DDLT recipients were diagnosed with hepatocellular carcinoma.

Table 1. Demographic Comparison Between LDLT and DDLT
 LDLTDDLTP
  1. Abbreviations: NS, not significant; HCC, hepatocellular carcinoma; ACR, acute cellular rejection; MELD, model for end-stage liver disease; f/u, follow-up.

Total number of patients1552 
Male10 (67%)41 (78.8%)NS
Female5 (33%)11 (21.2%)NS
Mean age51.4 ± 8.251.0 ± 5.4NS
Patients with HCC4 (26.7%)19 (36.5%)NS
Steroid-treated ACR2 (13.3%)8 (15.4%)NS
CTP score8.2 ± 1.29.1 ± 1.6NS
MELD score16.9 ± 6.919.0 ± 8.3NS
Mean f/u time (days)749 ± 371692 ± 347NS

A total 16 patients are excluded from the study. One LDLT recipient was retransplanted on day 4 due to hepatic artery thrombosis. Fifteen DDLT recipients were excluded for reasons as follows: 5 patients had less than 4 months' follow–up; 4 had no protocol liver biopsy (3 of 4 died of sepsis, acute renal failure, and multisystem organ failure, respectively); 1 died intraoperatively; 1 had ongoing acute cellular rejection at month-4 biopsy; and 4 had severe cytomegalovirus infection.

Viral Characteristics

The predominant genotype in both groups was genotype 1 (Fig. 1). Comparison of HCV genotype distribution showed no significant difference between the LDLT and DDLT groups. Recent data implies that HCV genotype 1b might be associated with a more aggressive clinical course in LT population. The genotype 1b distribution is 20.0% (3/15) in LDLT and 21.2% (11/52) in DDLT.

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Figure 1. HCV genotype distribution in LDLT and DDLT recipients. There were no statistical differences between the groups. LDLT gray bars represent LDLT recipients. Black bars represent DDLT recipients.

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HCV viral load was compared between the 2 groups. Again, the average viral load for DDLT and LDLT recipients showed no significant difference at pre-LT, 4 months, and 1 year after LT as indicated in our previous report.17 The average viral load significantly increased, up to 8-fold after transplantation, in both groups, and achieved a plateau 4 months post-LT (Fig. 2). However, the difference between the groups was not statistically significant.

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Figure 2. Average HCV viral load pre-LT and post-LT in LDLT and DDLT patients. Viral loads in the 2 patient populations were studied. The units in the X-axis unit are measured in IU/mL. Note the rapid rise in viral titers after LT with stabilization shortly after the procedure. Diamonds indicate LDLT. Squares indicate DDLT.

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Histological Recurrence Rate of Hepatitis C

The histological recurrence of HCV was examined and diagnosed based the criteria described above. Our patients had quick recurrence, with 90.0% in the LDLT and 94.8% in the DDLT group 1 year posttransplant and, as expected, almost universal recurrence at 2 years after LT in both groups (Table 2). More than half of recipients developed histological evidence of HCV recurrence in the first 4 months (Table 3). Our data do not support an earlier or more severe recurrence in the LDLT patient cohort.

Table 2. Accumulated Recurrence Rate of Hepatitis C
 4 Months1 Year2 YearsP
  1. NOTE: Denominators represent the total number of patients in each group.

  2. Abbreviation: NS, not significant.

LDLT8/15 (53.3%)9/15 (60%)12/15 (80.0%)NS
DDLT37/52 (71.2%)43/52 (82.7%)47/52 (90.4%)NS
Table 3. Recurrent Rate of Hepatitis C at 4-month, 1-year, and 2-year Follow-Up Evaluations
 Total4 Months1 Year2 YearsP
  1. NOTE: Denominators represent the total number of patients available for analysis at each time point.

  2. Abbreviation: NS, not significant.

LDLT12/15 (80.0%)8/15 (53.3%)9/10 (90%)5/5 (100%)NS
DDLT47/52 (90.4%)37/52 (71.2%)37/39 (94.8%)16/17 (95%)NS

Histological Analysis in Patients with Recurrent Hepatitis C

Histological analysis at 4 and 12 months post-LT showed a trend for lower histological hepatitis indices by Batts-Ludwig criteria in the LDLT recipient group vs. the DDLT recipient group (P = not significant) (Table 4, Fig. 3).

Table 4. Intrahepatic Inflammation and Fibrosis Activity Analysis
 LDLTDDLTP
  1. Abbreviation: NS, not significant.

Grade     
 4 months81.0371.27NS
 1 year91.4371.8NS
 2 years51.8161.5NS
Stage     
 4 months80.3370.4NS
 1 year90.8371.1NS
 2 years51.4161.2NS
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Figure 3. Comparison of Ishak score of (A) grade and (B) stage at 4 months, 1 year and 2 years between living donor and deceased donor recipients with recurrent hepatitis C. Gray bars represent LDLT patients. Black bars represent DDLT patients.

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Clinical Outcome and Survival

Two-year clinical course follow-up showed that there was no (0/15) recurrent HCV-related decompensated cirrhosis in the LDLT group, but 5.8% (3/52) in the DDLT group had this result. The 2-year patient survival for LDLT and DDLT was 14/15 (93%) and 50/52 (96%), respectively. The allograft survival was 87% in LDLT and 94% in DDLT recipients 2 years after liver transplantation (Fig. 4).

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Figure 4. Two-year (A) patient and (B) graft survival rate in different donor–type liver transplant recipients. Green lines represent LDLT. Blue lines represent DDLT. Vertical lines indicate that follow-up was censored.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Liver transplantation has become the standard management for advanced cirrhosis and early-stage hepatocellular carcinoma.21 The critical organ shortage has brought LDLT to the forefront in the management of our growing transplantation population. HCV-related liver transplant has become the leading indication for both in LDLT and DDLT.2 Initial reports of more rapid recurrence of HCV in the LDLT recipient population deserve careful attention.13, 14 The lack of consensus in the literature demands continued reports and clarification to assure better outcomes and more aggressive treatment.15, 16

Review of our pathological data from 67 patients at 4, 12, and 24 months post-LT in the DDLT and LDLT recipient groups failed to reveal a more aggressive course, or a higher and earlier recurrence rate of post-LT HCV in the LDLT group vs. the DDLT group as initially reported.17 Importantly, we have a protocol for liver biopsies that allows us to make careful comparison of the study groups. The results of the present study are consistent with recent reports from several American groups.15, 16, 18, 19

As many as 50% of all HCV recipients developed histological evidence of recurrent hepatitis at 4 months and reached 90% 1 year post-LT. This result indicates that recurrence of hepatitis C is an early event in both cohorts of immunosuppressed hosts, independent of graft source.

Why are there discrepancies in the outcomes in different centers? One explanation may center on the definition of recurrent hepatitis. We strongly encourage the wide application of the consensus criteria formulated by the International Liver transplantation Society.2 Clarity in definition of recurrent HCV, which should marry histological with biochemical parameters, is of utmost importance until less-invasive diagnostic parameters are developed. While hepatic regeneration factors may indeed facilitate the replication of HCV, it is also possible that the limited ischemic injury and healthy background of the grafts used in LDLT can compensate for the adverse effects of regeneration. Another possibility that cannot be overlooked is that our sample is small and thus subject to type II error, and we have missed the real possibility that the groups indeed differ over time. Since this is a single-center observation, this report will add to the data already published, and a continued call for large, multicenter, prospective trials needs to be reaffirmed.

Finally, our previous report17 indicated there was a significantly higher rejection rate in the DDLT recipient group compared to that of the LDLT recipient group. However, a closer look at this group revealed that there was similar percentage of patients whose rejection warranted treatment with corticosteroids (13.3% in LDLT vs. 15.4% in DDLT, P = not significant). As reported previously, no relationship was observed between the presence of rejection and the rate of HCV recurrence.17

In conclusion, there are no differences observed in hepatitis C recurrence rate, severity of intrahepatic pathology, or graft and patient survival between LDLT and DDLT recipients in our institution. Although there is a higher rejection rate in the DDLT recipient group, our results clearly indicate that the outcome of patients with histological recurrent hepatitis C in the LDLT group is not worse than the outcome of patients in the DDLT group.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES